Zh

quinone.51 The mechanism of DNA alkylation by these hydroquinones (6.29) is proposed to involve B-ring opening with assistance from the phenolic hydroxyl group to give quinone methides 6.30, which subsequently cyclize again to iminium derivatives 6.31, the actual DNA alkylating agents. The redox equilibrium between the saframycins and their semiquinones 6.28, as intermediates in the reduction of the natural products to hydroquinones 6.29, is also involved in the generation of cytotoxic oxygen radicals (Fig. 6.14). Finally, we will mention that glyceralde-hyde-3-phosphate dehydrogenase (GAPDH), a key transcriptional coactivator necessary for entry into S-phase due to its involvement in the maintenance and/or protection of telomeres, has been identified as a protein target of DNA-small molecule adducts of several members of the saframycin class. Additionally, GAPDH is also capable of forming a ternary complex with saframycin-related compounds and DNA that induces a toxic response in cells.52

A mechanism very similar to the one summarized in Fig. 6.14 accounts for DNA alkylation by bioxalomycin p2,53 although a second mode of alkylation at C-14 in structure 6.33 after quinone reduction and opening of the oxazolidine ring has been suggested following molecular modelling studies.54 In the case of bioxalomycins, it has been shown that the reduced form yields DNA interstrand h3c r--

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.